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Abstract:

A preparation for external use which, even when ingredients such as a
drug, absorption accelerator, and plasticizer are contained therein in a
large amount, is excellent in pressure-sensitive adhesive properties
including cohesive force and which, when a drug is contained therein,
enables the drug to have excellent percutaneous absorbability. The
preparation for external use includes a pressure-sensitive-adhesive
matrix layer, wherein the pressure-sensitive-adhesive matrix layer
comprises a pressure-sensitive adhesive base comprising a hydroxylated
polymer, a boron compound, and silicic acid.

Claims:

1. A method for producing a patch for percutaneous administration of a
drug, said method comprising mixing a dispersion comprising a boron
compound, silicic acid and a drug with a pressure-sensitive adhesive base
comprising a hydroxy group-containing polymer to promote formation of a
bond between the hydroxy group of the hydroxy group-containing polymer
and the boron compound via addition of the silicic acid.

2. The method of claim 1 further comprising stirring the resulting
mixture to produce a uniform coating liquid.

3. The method of claim 2 further comprising applying the uniform liquid
coating to a separator or a backing.

4. The method of claim 3 further comprising laminating the resulting
separator to a backing or the resulting backing to a separator to produce
a patch for percutaneous administration of the drug.

Description:

[0001] This patent application is a continuation of U.S. application Ser.
No. 12/064,246 filed Feb. 20, 2008, which is the National Stage of
International Application No. PCT/JP2006/316375 filed Aug. 22, 2006,
which claims the benefit of priority from Japanese Application No.
2005-239262 filed Aug. 22, 2005, teachings of each of which are herein
incorporated by reference in their entirety.

TECHNICAL FIELD

[0002] The present invention relates to a preparation for external use
having excellent cohesiveness and pressure-sensitive adhesion.

BACKGROUND ART

[0003] In recent years, a preparation for percutaneously administering a
drug (percutaneous absorption preparation) has been provided for some
drugs. There are various forms of the percutaneous absorption
preparation, but basically one having a backing and a pressure-sensitive
adhesive layer laminated thereon with a drug added to the
pressure-sensitive adhesive matrix layer is simple and has excellent
adherence to skin. The percutaneous absorption preparation has to be
adhered to the surface of a patient's skin so as to follow movement of
the skin, but if the preparation is adhered to the skin too strongly, it
causes inflammation to the skin when it is peeled off, thus an
appropriate pressure-sensitive adhesion is required.

[0004] In order for the medicinal efficacy expected by percutaneous
application of a drug to be exhibited more quickly and continuously, it
is necessary to realize a higher percutaneous absorption of the drug.
However, because skin generally functions as a barrier against a
penetrant from the environment, it is difficult for the drug to be
absorbed via the skin. In order to enhance the percutaneous absorption of
a drug, it is necessary to add the drug so that the concentration thereof
dissolved in a preparation is close to saturation and, moreover, to use a
medium having high affinity for the drug in order to promote diffusion of
the drug. However, if these two requirements are satisfied, physical
properties such as pressure-sensitive adhesion of the preparation are
easily impaired, and particularly for a drug having poor solubility it is
difficult to achieve a balance between drug absorption and
pressure-sensitive adhesion properties.

[0005] Attempts have been made to provide a preparation that gives both
excellent drug absorption properties and excellent pressure-sensitive
adhesion properties.

[0006] For example, there is a tape preparation formed by laminating on a
backing a pressure sensitive adhesive containing a basic drug having a
free base structure in an acrylic copolymer having a hydroxy group and/or
a carboxyl group in the molecule (ref. Patent Publication 1). There is a
patch in which a pressure-sensitive adhesive base contains a drug, a
plasticizing compound, hydrophilic anhydrous silicic acid, and
hydrophobic anhydrous silicic acid, using isopropyl myristate, a
polyhydric alcohol fatty acid ester, etc., as the plasticizing compound
(ref. Patent Publication 2).

[0007] In addition, in the production of a tape-form, etc. crosslinked
pressure-sensitive adhesive molding in which a hydroxy group or carboxyl
group-containing polymer and a crosslinking agent such as a
boron-containing compound are mixed, the crosslinking speed is controlled
by crosslinking in the presence of a lower alcohol, and an absorption
enhancer such as isopropyl myristate or a sorbitan fatty acid ester is
used (ref. Patent Publication 3).

[0008] There is a pressure sensitive adhesive composition for medical use
such as a patch containing an acrylic copolymer, a plasticizer, and a
pseudo-crosslinking agent, in which isopropyl myristate, etc. are used as
the plasticizer, and a borate such as ammonium borate is used as the
pseudo-crosslinking agent (ref. Patent Publication 4), and there is also
a composition such as a patch containing an acrylic copolymer having
hydroxyethyl (meth)acrylate as a component, a plasticizer, and a
pseudo-crosslinking agent, in which isopropyl myristate, etc. are used as
the plasticizer, and boric acid, ammonium borate, etc. are used as the
pseudo-crosslinking agent (ref. Patent Publication 5).

[0009] Although these techniques aim to relieve skin irritation and give
good drug absorption and pressure-sensitive adhesion, there is still the
unsolved problem that when a large amount of absorption enhancer or
plasticizer is added in order to enhance the drug absorption, the
cohesive strength of the pressure-sensitive adhesive matrix layer is
degraded, and desired pressure-sensitive adhesion properties cannot be
obtained.

[0010] Conventional techniques with regard to a percutaneous absorption
preparation of a drug having poor solubility, for example, tamsulosin or
a salt thereof, are now explained. Tamsulosin hydrochloride has the
function of blocking α1 receptors of the urethra and the prostatic
portion to thus decrease the internal pressure of the urethra in the
prostatic portion, and is commercially available in the form of tablets
or capsules as an agent for improving dysuria accompanying prostatic
hypertrophy.

[0011] For example, there is a preparation for external use such as a
patch containing amsulosin or a salt thereof, and an absorption enhancer
such as an aqueous alcohol or an aliphatic dicarboxylic acid diester
(ref. Patent Publication 6).

[0012] Furthermore, there is a percutaneous absorption preparation
containing tamsulosin free base that employs isopropyl myristate, etc. as
a percutaneous absorption enhancer (ref. Patent Publication 7), and there
is also a delivery system for a basic drug containing a laminated
composite of a reservoir layer containing a drug and a solubilization
improving agent composition, and a backing layer, which employs
tamsulosin as the drug and a skin penetration improving agent composition
such as an ester component or an acid component (ref. Patent Publication
8).

[0013] However, in these conventional techniques, a percutaneous
absorption preparation that gives excellent percutaneous absorption for
tamsulosin could not be obtained.

[0023] It is therefore an object of the present invention to solve the
conventional problems and to provide a preparation for external use that
has excellent pressure-sensitive adhesion properties such as cohesive
strength even when there are large amounts of components such as a drug,
an absorption enhancer, and a plasticizer, and that gives excellent
percutaneous absorption when it contains a drug.

Means for Solving the Problems

[0024] While carrying out an intensive investigation in order to solve the
above-mentioned problems, the present inventors have found that, a
pressure-sensitive adhesive matrix layer formed by adding a boron
compound and a silicic acid to a pressure-sensitive adhesive polymer
having a hydroxy group in the molecule can, even if a large amount of
absorption enhancer, etc. is added, maintain the cohesive strength of the
pressure-sensitive adhesive matrix layer and, moreover, when it contains
a drug, it can exhibit high absorbability, and as a result of further
research, the present invention has been accomplished.

[0025] That is, the present invention relates to a preparation for
external use that includes a pressure-sensitive adhesive matrix layer,
the pressure-sensitive adhesive matrix layer including a boron compound,
a silicic acid, and a pressure-sensitive adhesive base that includes a
hydroxy group-containing polymer.

[0026] Furthermore, the present invention relates to the preparation for
external use, wherein it has a backing.

[0027] Moreover, the present invention relates to the preparation for
external use, wherein the boron compound is boric acid.

[0031] Moreover, the present invention relates to the preparation for
external use, wherein it further includes an absorption enhancer and/or a
plasticizer.

[0032] Furthermore, the present invention relates to the preparation for
external use, wherein the absorption enhancer is one or more selected
from the group consisting of a fatty acid, a fatty acid salt, a fatty
acid ester, and a fatty acid amide.

[0033] Moreover, the present invention relates to the preparation for
external use, wherein the absorption enhancer is one or more selected
from the group consisting of acetic acid, capric acid, sodium acetate,
isopropyl myristate, sorbitan monooleate, sorbitan monolaurate, and
lauric acid diethanolamide.

[0034] Furthermore, the present invention relates to the preparation for
external use, wherein it gives a maximum blood drug concentration/minimum
blood drug concentration ratio after being administered once a day
continuously of 1.0 to 1.2.

[0035] Moreover, the present invention relates to the preparation for
external use, wherein it gives a maximum blood drug concentration/minimum
blood drug concentration ratio after being administered repeatedly with
one day administration and one day suspension of the drug of 1.0 to 1.3.

[0036] Furthermore, the present invention relates to the preparation for
external use, wherein it gives a maximum blood drug concentration/minimum
blood drug concentration ratio after being administered once every 3.5
days continuously of 1.0 to 1.3.

[0037] Moreover, the present invention relates to the preparation for
external use, wherein it gives a maximum blood drug concentration/minimum
blood drug concentration ratio after being administered once every 7 days
continuously of 1.0 to 1.3.

Effects of the Invention

[0038] In accordance with the present invention, even with a large amount
of a drug and another component such as an absorption enhancer, a
preparation for external use is provided in which the pressure-sensitive
adhesive matrix layer has excellent cohesiveness, and if it contains a
drug, the drug absorbability is excellent. Furthermore, the present
invention gives excellent cohesive strength for the pressure-sensitive
adhesive matrix layer and drug absorbability even when a drug having poor
solubility such as tamsulosin or an acid addition salt thereof is used.

[0039] Since a patch of the present invention has excellent sustained drug
release properties and can reduce the maximum blood drug
concentration/minimum blood drug concentration ratio P/T, side effects of
the drug can be suppressed and, moreover, since the blood drug
concentration can be made to stay more or less constant, the effect can
be sustained.

BRIEF DESCRIPTION OF DRAWINGS

[0040]FIG. 1 shows a simulation of plasma concentration when patches of
the present invention and commercial products are administered.

BEST MODE FOR CARRYING OUT THE INVENTION

[0041] The preparation for external use of the present invention is
constituted from a pressure-sensitive adhesive matrix layer, and the
pressure-sensitive adhesive matrix layer contains a boron compound, a
silicic acid, and a pressure-sensitive adhesive base formed from a
polymer having a hydroxy group in the molecule.

[0042] It is surmised that the preparation for external use of the present
invention is formed by some kind of interaction between the silicic acid
and a chemical bond of the hydroxy group of the pressure-sensitive
adhesive base with the boron compound, thereby retaining other components
contained therein, such as a drug, in the layer shape, thus enhancing
cohesive strength.

[0043] Each component of the preparation for external use of the present
invention is explained in more detail below.

[0044] The preparation for external use of the present invention may have
a backing, and the pressure-sensitive adhesive matrix layer is laminated
on one side of the backing. The backing used here is a sheet-form
material that physically supports the pressure-sensitive adhesive matrix
layer and protects the pressure-sensitive adhesive matrix layer from the
external environment. It is therefore necessary for the backing to have a
physical support function in order to handle the preparation by hand or
affix it to the skin, and it is not desirable that a component of the
pressure-sensitive adhesive matrix layer penetrates into the backing or
that the backing is torn when the preparation is peeled off from the
skin. As the backing, a film, a fabric, a porous sheet, a paper, or a
laminate thereof may be used, and a film is most preferable. With regard
to a material of the backing, a polyester such as polyethylene
terephthalate or polybutylene terephthalate, a polyolefin such as
polyethylene or polypropylene, nylon, rayon, polyurethane, or a metal
foil such as aluminum foil may be used, and a polyester is most
preferable from the viewpoint of flexibility for following the movement
of the skin, and resistance to drug, etc. penetration.

[0045] The pressure-sensitive adhesive matrix layer forming the
preparation for external use of the present invention is a layered
material formed from a mixture that is laminated on one side of the
backing, adheres to the skin by having pressure-sensitive adhesion, and
supplies a drug contained therein to the skin surface. The
pressure-sensitive adhesive matrix layer contains at least a boron
compound, a silicic acid, and a pressure-sensitive adhesive base formed
from a polymer having a hydroxy group in the molecule, and may contain as
appropriate another component such as a drug, a tackifying resin, a
plasticizer, a filler, an absorption enhancer, a solubilizing agent, or a
stabilizer. The thickness of the pressure-sensitive adhesive matrix layer
is preferably in the range of 20 to 200 μm. Such a range can give
sufficient cohesive strength for retaining the shape and good
pressure-sensitive adhesion to the skin.

[0046] The drug contained in the pressure-sensitive adhesive matrix layer
forming the preparation for external use of the present invention is the
main constitution that is absorbed from the pressure-sensitive adhesive
matrix layer into the body via the skin, and exhibits a physiological
effect. The drug is selected according to an intended treatment and is
not particularly limited, and examples thereof include a drug acting on
the peripheral nervous system, a drug acting on the sympathetic nervous
system, a drug acting on the parasympathetic nervous system, a drug
acting on the autonomic ganglia, a drug for sensory nerves, a general
anesthetic, a sedative, an anti-dementia drug, an anesthetic, an
analgesic, an antipyretic anti-inflammatory analgesic, a steroid hormone,
an analeptic/stimulant, a drug for psychoneurosis, a local anesthetic, a
skeletal muscle relaxant, a drug for the autonomic nervous system, an
antiallergic drug, an antihistamine, a cardiotonic, a drug for
arrhythmia, a diuretic, a hypotensive drug, a vasoconstrictor, a
vasodilator, a calcium antagonist, a disinfectant, a drug for parasitic
skin disease, an emollient, an antibiotic, an antidote, an antitussive
expectorant drug, an antipruritic, a hypnotic, an antiasthmatic drug, a
hormone secretagogue, an antiulcer drug, an antitumor drug, a vitamin, a
cholinergic drug, an acetylcholinesterase inhibitor, estrogen,
progesterone, an antifungal drug, an anti-parkinsonism drug, an
antiemetic, and a psychotropic drug.

[0047] Examples of the drug include a drug for dysuria such as tamsulosin
or oxybutynin, a β-blocker such as propranolol, pindolol,
metoprolol, bisoprolol, or labetalol, an α-blocker such as
prazosin, terazosin, or doxazosin, a β-stimulant such as
tulobuterol, and salts of these drugs. Among the drugs described above,
excellent effects are exhibited with, for example, tamsulosin and
pharmaceutically acceptable acid addition salts thereof, which have poor
solubility. The pharmaceutically acceptable acid addition salts referred
to here include the hydrochloride (formula below), the mesylate, and the
citrate, and the hydrochloride is particularly suitably used.

##STR00001##

Tamsulosin hydrochloride is an α1 receptor blocker and is
prescribed for the purpose of improving dysuria.

[0048] The drug is normally preferably added in the range of 1 to 30 mass
% relative to the entire pressure-sensitive adhesive matrix layer. When
the above-mentioned tamsulosin and acid addition salt thereof are used,
the amount thereof added should be determined as appropriate according to
an administration plan, but when the therapeutic effect is taken into
consideration it is preferably in the range of 1 to 30 mass % relative to
the entire pressure-sensitive adhesive matrix layer.

[0049] Furthermore, the molecular weight of the drug used is suitably 600
or below when percutaneous absorbability is taken into consideration.

[0050] The drug and the pressure-sensitive adhesive base used in the
preparation for external use of the present invention are selected as
appropriate, mainly based on the relationship between the characteristics
of the chemical structure of the drug and a functional group of the
pressure-sensitive adhesive base rather than on the physiological effect
of the drug. In the preparation for external use of the present
invention, if the pressure-sensitive adhesive base has a carboxyl group
and the drug is an amine-based drug, hardly any drug is delivered to the
body. It appears that this is because the carboxyl group of the
pressure-sensitive adhesive base and an amino group of the drug form an
ionic bond, thereby greatly suppressing diffusion of the drug in the
pressure-sensitive adhesive matrix layer. Therefore, a combination of the
pressure-sensitive adhesive base and the drug should be selected so that
such an ionic bond is not formed. That is, when the pressure-sensitive
adhesive base does not have an acidic dissociable functional group, the
drug may be non-ionically dissociable or have a basic dissociable group.
When the pressure-sensitive adhesive base does not have an ionic
dissociable group, the drug may be non-ionically dissociable or have any
dissociable group such as an acid or a base. When the pressure-sensitive
adhesive base does not have a basic dissociable functional group, the
drug may be non-ionically dissociable or may have an acidic dissociable
group. The acidic dissociable functional group referred to above is a
carboxyl group, a sulfonic acid group, etc., and examples of the basic
dissociable functional group include a primary amino group, a secondary
amino group, a tertiary amino group, and a quaternary ammonium group.

[0051] The polymer having a hydroxy group in the molecule, which is used
as the pressure-sensitive adhesive base of the pressure-sensitive
adhesive matrix layer forming the preparation for external use of the
present invention, is formed by some type of bond between the hydroxy
group, the boron compound, and the silicic acid, although the mechanism
is not clear, thereby retaining other components, such as a drug
contained in the pressure-sensitive adhesive matrix layer in the layered
shape, allows these components to diffuse and move to the skin surface,
and provides pressure-sensitive adhesion to the skin. The polymer is
preferably a vinyl-based polymer having a hydroxy group in the molecule.
The vinyl-based polymer having a hydroxy group in the molecule is
preferably a (meth)acrylic acid ester copolymer or vinyl acetate
copolymer having a hydroxy group in the molecule, etc.

[0052] The (meth)acrylic acid ester copolymer has an acrylic acid ester or
methacrylic acid ester as a main monomer, an acrylic acid ester or
methacrylic acid ester monomer having a hydroxy group as its crosslinking
site is copolymerized, and another monomer may be copolymerized in order
to modify the pressure-sensitive adhesion properties, etc. of the base.

[0054] The hydroxy group-containing acrylic acid ester or methacrylic acid
ester monomer of the (meth)acrylic acid ester copolymer is preferably an
acrylic acid ester or methacrylic acid ester such as 2-hydroxyethyl
acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate,
2-hydroxyethyl methacrylate, 3-hydroxypropyl methacrylate, or
4-hydroxybutyl methacrylate, vinyl alcohol, allyl alcohol, 3-buten-1-ol,
3-buten-2-ol, etc. The proportion of the hydroxy group-containing monomer
is preferably in the range of 1 to 15 mol % relative to the entire
copolymer. The hydroxy group forms a bond with the boron compound and the
silicic acid and functions as a crosslinking site of the
pressure-sensitive adhesive matrix layer. However, it is undesirable to
have a large amount of the hydroxy group-containing monomer since it
degrades the pressure-sensitive adhesion of the matrix layer.

[0056] A monomer having a carboxyl group such as acrylic acid or
methacrylic acid is preferably not copolymerized with the (meth)acrylic
acid ester copolymer, and since such a monomer tends to inhibit release
of the drug from the preparation, if one is added, it should be added at
5% or below.

[0057] Examples of the pressure-sensitive adhesive base of the
pressure-sensitive adhesive matrix layer of the present invention include
commercial pressure sensitive adhesives such as Duro-Tak 87-2287
(manufactured by Nippon NSC Ltd.).

[0058] The proportion of the polymer having a hydroxy group in the
molecule is preferably at least 25 mass % relative to the entire
pressure-sensitive adhesive matrix layer (the same applies below), and in
this range sufficient cohesive strength is obtained for the
pressure-sensitive adhesive matrix layer.

[0059] In addition to the above-mentioned pressure-sensitive adhesive
base, in order to modify the pressure-sensitive adhesion properties of
the pressure-sensitive adhesive matrix layer or absorption of the drug,
an additional pressure-sensitive adhesive base may be added. From the
viewpoint of drug absorption, the additional pressure-sensitive adhesive
base is preferably a polymer that does not have a dissociable group with
a charge that forms a pair with the ionically dissociable charge of the
drug. Specific examples thereof include non-ionically dissociable
polymers such as polyvinylpyrrolidone, a vinylpyrrolidone copolymer,
polyisobutylene, polyisoprene, polyvinyl acetate, a vinyl acetate
copolymer such as an ethylene-vinyl acetate copolymer, a
styrene-butadiene-styrene block copolymer, a styrene-isoprene-styrene
block copolymer, and a styrene-butadiene rubber. The proportion of the
additional pressure-sensitive adhesive base is preferably no greater than
60 mass % relative to the entire pressure-sensitive adhesive matrix
layer, and in such a range the cohesive strength of the
pressure-sensitive adhesive matrix layer is not degraded.

[0060] The boron compound used in the preparation for external use of the
present invention forms an ester bond with the hydroxy group of the
pressure-sensitive adhesive base to thus become a crosslinking site of
the pressure-sensitive adhesive matrix layer, thereby enhancing the
cohesive strength of the pressure-sensitive adhesive matrix layer. As the
boron compound, a borate such as sodium tetraborate or ammonium
tetraborate or, furthermore, a boron compound having a valence of +3 such
as boric acid, methyl borate, ethyl borate, propyl borate, or butyl
borate may be employed, and boric acid is preferable. Boric acid is a
compound represented by H3BO3, and anhydrous boric acid or a
hydrate may be used.

[0061] In order to uniformly prepare a pressure-sensitive adhesive matrix
layer of the preparation for external use of the present invention, boric
acid is mixed with another component once it has been dissolved in a
solvent, thus achieving uniform crosslinking. The boric acid may be
dissolved in water, an alcohol, glycerol, etc. Among the above solvents,
methanol or ethanol is preferable.

[0062] The amount of boron compound added is preferably in the range of 1
to 8 mass % relative to the entire pressure-sensitive adhesive matrix
layer, and in such a range the cohesive strength can be enhanced and
sufficient pressure-sensitive adhesion can be obtained for the
pressure-sensitive adhesive matrix layer.

[0063] The silicic acid used in the preparation for external use of the
present invention promotes formation of a bond between the hydroxy group
and boric acid, imparts shape retention to the pressure-sensitive
adhesive matrix layer by physical bonding between silicic acid particles,
and enhances the cohesive strength. Examples of the silicic acid include
silica gel produced from sodium silicate, colloidal silica (dispersion),
which is ultra-fine particles of anhydrous silicic acid produced from
water glass, and ultra-fine particulate anhydrous silica (light anhydrous
silicic acid) produced in the gas phase from a chloride of ferrosilicon.
Among them, anhydrous silicic acid is preferable to hydrated silicic
acid, and light anhydrous silicic acid is more preferable.

[0064] The particle size of the silicic acid is preferably small; the
average particle size is preferably no greater than 50 μm, and
particularly preferably no greater than 16 μm. In this range, there is
hardly any coating unevenness when preparing a pressure-sensitive
adhesive matrix; material having a small particle size has a large
surface area and an excellent effect in enhancing drug absorption, and
also has excellent effects in retaining the shape of the
pressure-sensitive adhesive matrix layer and enhancing the cohesive
strength.

[0065] With regard to anhydrous silica particles, those having a
hydrophilic surface are preferable in terms of drug absorption, and give
good mixing properties with a medium (solvent) when preparing the
pressure-sensitive adhesive matrix.

[0066] The amount of silicic acid added is preferably in the range of 0.2
to 10 mass % relative to the entire pressure-sensitive adhesive matrix
layer, and in this range a liquid to be applied has a good flowability
when preparing the pressure-sensitive adhesive matrix, and the
pressure-sensitive adhesive matrix thus obtained has a uniform thickness.

[0067] The specific surface area of the particles is preferably at least
100 cm2/g, and more preferably at least 300 cm2/g, from the
viewpoint of enhancement of the shape retention of the pressure-sensitive
adhesive matrix layer.

[0068] With regard to the silicic acid, for example, 7 to 16 μm light
anhydrous silicic acid is commercially available and preferably used.

[0069] Although the reason that adding the silicic acid promotes a
crosslinking reaction of the boron compound is not clear, it is surmised
that the boron compound is bonded to --OSi═O or --OSiOH of the
surface of anhydrous silicic acid to thus increase the electrophilicity
of the B atom, thereby making it easy to form a crosslinking bond with
the oxygen atom of the OH of the pressure-sensitive adhesive base. It is
also surmised that a crosslinking site is formed by an ester exchange
reaction that forms a bond between the oxygen atom of the OH of the base
polymer and anhydrous silicic acid.

[0070] Since the above-mentioned reaction progresses gradually, there is
enough time between mixing these compounds and spreading the liquid into
a sheet form, thus making it convenient for the production of a patch.

[0071] With the above-mentioned compounds, the preparation for external
use of the present invention has excellent cohesive strength and
appropriate pressure-sensitive adhesive power.

[0072] The present invention may further contain a percutaneous absorption
enhancer in order to enhance the drug absorption. The above-mentioned
compounds enable the preparation for external use of the present
invention to maintain the cohesive strength of the pressure-sensitive
adhesive matrix layer even when it contains a large amount of another
component such as a percutaneous absorption enhancer, thus high drug
absorption can be achieved.

[0073] The absorption enhancer may be used in order to enhance absorption
of the drug. The absorption enhancer that can be used is not particularly
limited and is selected from known absorption enhancers according to the
drug administration form. Specific examples thereof include lower
alcohols, saturated or unsaturated straight-chain or branched aliphatic
alcohols, saturated or unsaturated aliphatic ethers, saturated or
unsaturated fatty acids, fatty acid salts, fatty acid esters such as a
sorbitan fatty acid ester or a fatty acid glycerol ester, fatty acid
ester amides, terpenes, vegetable oils or fats such as olive oil, animal
oils or fats such as squalene, N-methylpyrrolidone, crotamiton, and
azacycloalkane derivatives.

[0074] Examples of the saturated or unsaturated fatty acids include
organic acids having 2 to 4 carbons such as acetic acid, propionic acid,
butyric acid, lactic acid, glycolic acid, malic acid, tartaric acid, and
citric acid, and fatty acids such as straight-chain or branched saturated
fatty acids having 6 to 18 carbons such as caproic acid, caprylic acid,
capric acid, lauric acid, myristic acid, palmitic acid, stearic acid,
linoleic acid, and linolenic acid, or unsaturated fatty acids such as
oleic acid, linoleic acid, and linolenic acid, and acetic acid, capric
acid, lauric acid, etc. are preferably used. Examples of the fatty acid
salts include potassium, sodium, calcium, and magnesium salts of the
above-mentioned fatty acids; sodium acetate, sodium caprate, sodium
laurate, etc. are preferably used, and sodium acetate is particularly
preferable. Examples of the fatty acid esters includes esters formed from
the above-mentioned fatty acids and, as an alcohol, an aliphatic alcohol
such as methanol, ethanol, or propanol, a polyhydric alcohol such as
ethylene glycol, propylene glycol, glycerol, or polyethylene glycol, or a
sugar alcohol such as sorbitol and, for example, isopropyl myristate,
sorbitan monooleate, sorbitan monolaurate, etc. are preferable. With
regard to the fatty acid amides, amides between the above-mentioned fatty
acids and an amine such as diethanolamine, for example, lauric
diethanolamide, are preferable.

[0075] When the drug to be administered is tamsulosin or tamsulosin
hydrochloride, the absorption enhancer is preferably a fatty acid, a
fatty acid salt, a fatty acid ester, or a fatty acid amide. As the fatty
acid, acetic acid, capric acid, lauric acid, etc. are preferably used,
and acetic acid and capric acid are particularly preferable. As the fatty
acid salt, sodium acetate, sodium caprate, sodium laurate, etc. are
preferably used, and sodium acetate is particularly preferable. As the
fatty acid ester, isopropyl myristate, sorbitan monooleate, and sorbitan
monolaurate are preferable. As the fatty acid amide, lauric
diethanolamide is preferable. Among them, in the case of tamsulosin,
acetic acid is particularly preferable, and in the case of tamsulosin
hydrochloride, sodium acetate and capric acid are preferable.

[0076] The proportion of the absorption enhancer is preferably in the
range of 1 to 30 mass % relative to the entire pressure-sensitive
adhesive matrix layer, and in such a range it does not cause any residual
adhesive due to degradation of the cohesive strength of the
pressure-sensitive adhesive matrix layer.

[0077] The pressure-sensitive adhesive matrix layer of the present
invention may further contain as an additional component, for example, a
tackifying resin, a plasticizer, a filler, a solubilizing agent, a
stabilizer, etc.

[0078] The tackifying resin is used for enhancing the pressure-sensitive
adhesion of the pressure-sensitive adhesive matrix layer. The tackifying
resin that can be used is not particularly limited, and is selected from
known tackifying resins according to the drug administration mode.
Specific examples thereof include an alicyclic saturated hydrocarbon
resin, a hydrogenated rosin glycerol ester, an aliphatic hydrocarbon
resin, and a terpene resin. The proportion of the tackifying resin is
preferably no greater than 40 mass % relative to the entire
pressure-sensitive adhesive matrix layer.

[0079] The plasticizer may be used in order to modify the
pressure-sensitive adhesion properties of the pressure-sensitive adhesive
matrix layer, the flow properties of a coating solution in the production
thereof, and the drug absorption. By adding a plasticizer, the cohesive
strength of the pressure-sensitive adhesive matrix layer is degraded, and
flexibility is imparted. The plasticizer that can be used is not
particularly limited, and is selected from known plasticizers and
softening agents according to the drug administration form. Specific
examples thereof include liquid paraffin, liquid polybutene, liquid
polyisoprene, castor oil, cottonseed oil, palm oil, and coconut oil. The
proportion of the plasticizer is preferably no greater than 40 mass %
relative to the entire pressure-sensitive adhesive matrix layer.

[0080] The filler may be used mainly for modifying the pressure-sensitive
adhesion properties of the pressure-sensitive adhesive matrix layer, or
for shielding light. Adding a filler suppresses the pressure-sensitive
adhesive power. The filler that can be used is not particularly limited
and is selected from known fillers according to the drug administration
mode. Specific examples thereof include metal oxides such as zinc oxide
and titanium oxide, metal hydroxides such as aluminum hydroxide, silicate
compounds, and calcium carbonate. The proportion of the filler is
preferably no greater than 10 mass % relative to the entire
pressure-sensitive adhesive matrix layer, and care must be taken with the
proportion so that the filler does not inhibit crosslinking of the
pressure-sensitive adhesive matrix layer.

[0081] The solubilizing agent has the function of enhancing the drug
absorption by increasing the solubility of the drug in the
pressure-sensitive adhesive matrix layer. By adding a solubilizing agent,
the cohesive strength of the pressure-sensitive adhesive matrix layer is
often degraded. The solubilizing agent that can be used is not
particularly limited, and is selected as appropriate from known
solubilizing agents according to the drug.

[0082] With regard to the stabilizer, in order to enhance the stability of
the pressure-sensitive adhesive matrix layer or the drug, a known
antioxidant, UV absorber, etc. may be added as appropriate. Specific
examples of the stabilizer include ascorbic acid derivatives, tocopherol
derivatives, dibutylhydroxytoluene, an edetate, and
4-tert-butyl-4'-methoxydibenzoylmethane.

[0083] A separator used for the preparation for external use of the
present invention is laminated so as to cover the pressure-sensitive
adhesive matrix in order to protect it during storage and is peeled off
when using the preparation for external use. The separator may be a film,
a paper, or a laminate thereof, and is not particularly limited, and a
film is most preferable. Specific examples of the material of the
separator include a polyester such as polyethylene terephthalate,
polybutylene terephthalate, or polyethylene naphthalate, a polyolefin
such as polyethylene or polypropylene, a nylon, and a metal foil such as
an aluminum foil, and from the viewpoint of stability over time of the
physical properties of the preparation, a polyester is most preferable.
The surface of the separator is preferably subjected to a release
treatment such as a silicone treatment in order to facilitate peeling
off.

[0084] With regard to the preparation for external use of the present
invention, for example, the maximum blood drug concentration/minimum
blood drug concentration ratio P/T when it is administered once a day
continuously is preferably 1.0 to 1.2, the P/T ratio after being
administered repeatedly with one day administration and one day
suspension of the drug is preferably 1.0 to 1.3, the P/T ratio after
being administered once every 3.5 days continuously is preferably 1.0 to
1.3, and the P/T ratio after being administered once every 7 days
continuously is preferably 1.0 to 1.3, from the viewpoint of alleviation
of side effects of the drug and sustaining the effect. The maximum blood
drug concentration and the minimum blood drug concentration are values
obtained by measuring the blood drug concentration when the change in
drug concentration in the blood attains a fixed pattern while the drug is
repeatedly administered under the respective administration conditions,
that is, the pattern of change reaches a steady state.

EXAMPLES

[0085] The present invention is further explained below by reference to
Examples of the present invention, but the present invention is not
limited thereto and may be modified in a variety of ways.

Test 1

Patch Preparation Method

[0086] (1) Boric acid was added to methanol to give a 10 mass % solution.
(2) 0.40 g of Aerosil (AEROSIL 200) and 2.25 g of ethyl acetate were
added to 3.32 g of the solution from (1), and mixed for several minutes
to give a uniform dispersion. (3) 9.7 g of Duro-Tak 87-2287 liquid was
further added to the dispersion from (2), and mixed for about 1 hour. (4)
0.25 g of tamsulosin hydrochloride, 0.07 g of sodium acetate, 0.25 g of
isopropyl myristate (IPM), and 0.15 g of sorbitan monolaurate (SML) were
mixed for about 15 hours, 11.78 g of the liquid from (3) was further
added thereto, and mixing was carried out for about 1 hour to give a
uniform coating liquid. (5) The liquid from (4) was spread over a
silicone-treated surface of a separator (polyethylene terephthalate film,
75 μm), and dried at 80° C. for 10 minutes. Subsequently, a
backing (polyethylene terephthalate film, sand matte treated, 25 μm)
was laminated, thus giving a patch of Example 4 of the present invention.

[0087] Patches having the mixing proportions below were prepared in the
same manner as in Example 4. The mixing proportions are expressed as mass
%.

[0088] An appropriate size of a patch was affixed to a 100 g ring-shaped
load and set in a probe tack tester in accordance with ASTM D-2979, a
stainless steel probe having a diameter of 5 mm was pressed against the
pressure-sensitive adhesive surface of the patch for 1 sec at a speed of
5 mm/sec, and the force [gf] required for peeling off the probe at a
speed of 5 mm/sec was measured.

Peel Test

[0089] A 1 cm×5 cm patch was affixed to a stainless steel plate,
allowed to stand for 30 minutes, and then set in an Instron type tensile
tester, and the force [gf] required for peeling off at 180° at 300
mm/min was measured.

Skin Permeation Test

[0090] The skin of the ventral part of a hairless mouse was exfoliated
off, and mounted on a flow through cell with hot water at 37° C.
circulating around its outer periphery so that the dermal side was on a
receptor layer side. Subsequently, a patch with an application area of 5
cm2 was administered to the stratum corneum side of the skin, PBS
was used as the receptor layer, and PBS was flowed at 4.5 mL/hr as the
receptor layer and the receptor layer was sampled every 2 hours up to 24
hours. The flow rate was measured, the drug concentration was measured
using high performance liquid chromatography, a drug permeation rate per
hour was calculated from the measured values, and the maximum value
(Jmax) μg/cm2/hr was determined.

[0092] The preparation for external use of the present invention did not
show cohesive failure, had excellent cohesive strength and appropriate
pressure-sensitive adhesion, and when it contained a drug high
percutaneous absorption was exhibited.

[0093] Patches were prepared in the same manner as in Example 4 at the
mixing proportions below using tamsulosin free base instead of tamsulosin
hydrochloride.

[0098] The preparation for external use of the present invention did not
show cohesive failure, and had excellent percutaneous absorption.

Test 2

[0099] Actual residue from the preparation for external use of the present
invention was examined.

Test Method

[0100] The back of Japanese white rabbits was clipped and shaved, and 4
cm2 preparations of Example 3, Example 7, Comparative Example 4, and
Comparative Example 14 were administered.

[0101] Jackets were put on the rabbits, the preparations were peeled off
after 72 hours, and the residue was examined.

Animal species: Jw (Japanese white rabbit) female Age: 19 to 20 weeks

N=4

[0102] The results showed that there was no residue for Example 3 and
Example 7, and there was residue (cohesive failure) for Comparative
Example 4 and Comparative Example 14.

[0103] It was thus shown that the patch of the present invention did not
show cohesive failure when used in practice, whereas in the case of one
containing only 5% of boric acid, when it was actually administered to
the skin (rabbit) for 3 days there was residue (cohesive failure).

[0104] The concentrations of tamsulosin hydrochloride in plasma when the
patch of Example 41 of the present invention is administered by being
continuously administered and when there is a drug suspension period were
compared with the plasma concentration when a commercial product 1 and a
commercial product 2, which are preparations of tamsulosin hydrochloride,
are administered orally once a day. FIG. 1 shows the results. Comparing
the administration once a day continuously of Example 41 with the
commercial products, the patch of the present invention showed less
change in blood drug concentration, that is, the P/T ratio was small.
Furthermore, it can be seen that the patch of the present invention
showed less change in blood drug concentration even when a drug
suspension period was provided with one day administered and one day
suspension of the drug as in (2), while maintaining a certain level of
drug concentration.

INDUSTRIAL APPLICABILITY

[0105] The preparation for external use of the present invention is used
in the pharmaceutical industry for the purpose of preventing or treating
a disease. Furthermore, the preparation for external use containing
tamsulosin or an acid addition salt thereof is used in the pharmaceutical
industry for the purpose of improving dysuria accompanying prostatic
enlargement.